Copper-catalyzed enantioselective allylic substitution reactions

ABSTRACT

An allylic compound is reacted with an organozinc compound Zn(R 6 ) 2  to eliminate a group (the leaving group) from the allylic compound and to add a group from the organozinc compound to it in the presence of a copper salt catalyst and a chiral organic ligand for the copper. A novel ferrocenyl compound and a novel copper complex of the ferrocenyl compound and copper are also described.

This application is the national phase of international application PCT/GB99/0287 filed Aug. 25, 1999, which designated the U.S.

This invention relates to selective synthesis and catalysts therefor.

According to the invention an allylic compound is reacted with an organozinc compound Zn(R⁶)₂ to eliminate a group (the leaving group) from the allylic compound and to add a group from the organozinc compound to it in the presence of a copper salt catalyst and a chiral organic ligand for the copper. Preferably the ligand is a primary or secondary amine in which the nitrogen atom is directly linked to the chiral centre. The allylic compound is suitably of formula

where X is the leaving group for example a chlorine atom and in which A is hydrogen or an alkyl or aryl group, preferably having 1-20 carbon atoms. If substitution occurs at the carbon atom marked * a chiral centre may be formed. This process is known as Sn2′ substitution; an alternative substitution at the carbon atom marked † may occur in which case there may be no chiral centre, this process is known as Sn2 substitution.

The reactions are shown as follows:

where R⁶ is a group from the organozinc compound. Surprisingly, in this process the former reaction is generally favoured and is influenced by the leaving group, ligands and solvents as shown below, tetrahydofuran being a particularly favourable solvent. The process is normally chemoselective for Sn2′ substitution and/or stereoselective.

In a preferred form of the invention the reaction is as shown below:

R¹-R⁶ are alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl groups optionally substituted by for example halogen, alkoxy, aryloxy, acyloxy, nitro, amide, acetamide, carboxylate, cyano, acetal, sulphide, sulphonate, sulfone, sulfoxide, phosphite, phosphonate, phosphine groups, each preferably having at most 20 and preferably less than 10 carbon atoms, or R¹ to R⁵ may be H, R⁷ is an aryl for example a phenyl or ferrocenyl or substituted aryl or ferrocenyl group of which the substituents may be for example 1-aminobenzyl, 1-amino-2-naphthylmethyl, 1-amino-(4-tert-butylphenyl)methyl, trimethylsilyl, phosphite, phosphine, alkyl, alkoxy, thiophosphonate, amino and/or halogen (eg Cl or Br) atoms and R⁸ is an alkyl or aryl, preferably a methyl, ethyl, propyl, tert-butyl, phenyl or naphthyl for example 2-naphthyl group which may be substituted for example by nitro, alkoxy, alkyl and/or haloalkyl group. X is halogen, OR⁹, OCOR⁹, OCO₂R⁹, OSO₂R⁹, OCS₂R⁹ CH(OR¹⁰)₂, OPO(OR⁹)₂, SOR⁹, or SO₂R⁹ where R⁹ and R¹⁰ are optionally substituted C₁-C₁₀ alkyl or aryl, of which the substituents may be halogen, nitro, methoxy, trifluoromethoxy, methyl, ethyl, tert butyl or sulphonate groups e.g. methyl, ethyl, trifluoromethyl, phenyl, tosyl, p-bromophenyl, p-nitrophenyl, p-methoxyphenyl, or R7 and R8 may together form a 5 or 6 membered carbocyclic or heterocyclic ring providing that a carbon atom to which the nitrogen is attached is chiral. for example R7 and R8 together may be 1-indane, bornylamine or 2-cyclohexylamine. Y is halogen, carboxylate for example, acetate, acetoacetate, cyanide, or thiocyanate and Z is an ether or thioether for example dimethylsulfide, tetrahydrofuran or diethylether. Preferably R¹-R² and R³ and one of R⁴ or R⁵ are H and the other one of R⁴ or R⁵ is aryl, for example phenyl, 4-chlorophenyl or 4-trifluoromethyl phenyl or is a trialkyl (e.g. tri-isopropyl) silyl oxymethyl groups R⁶ is alkyl, tri-alkyl (e.g. trimethyl) silyl methyl, phenyl or 2,2-dimethylbut-3-enyl. R⁷ is ferrocenyl, R⁸ is naphthyl, X is chloride, Y is chloride or bromide and Z is dimethylsulfide. R⁵ is preferably phenyl and R⁶ is preferably neopentyl. The substituents of R⁷ preferably have at most 10 carbon atoms in total and those of R⁸ preferably at most 8 carbon atoms in total. Alkanes, cyclo alkanes and/or aromatic solvents for example toluene may be present.

Preferred solvents are ethers for example diethylether, 1,4-dioxane, tertbutylmethylether and especially tetrahydrofuran. Preferred temperatures are −120° C. to 25° C. more preferably −100° C. to 20° C. and especially −90° C. to −50° C.

Preferred concentrations of catalyst are 0.1 atom % to 20 atom %, especially 0.5 atom % to 5 atom % expressed as copper atoms based on moles of the allylic compound.

The ratio of copper atoms to the amine ligand molecules is suitably 1:10 to 2:1.

Compounds for formula

in which A is a ferrocenyl or substituted ferrocenyl group and B is a group R⁸ other than a methyl or phenyl group are believed to be novel. The groups A and B should be different in order to obtain stereospecificity. B is preferably a 2-naphthyl group.

EXAMPLE 1 Preparation of (R)-(1-amino-2-naphthylmethyl)Ferrocene

Step 1

Ferrocene (4.5 g, 24 mmol) and aluminium trichloride (3.5 g, 26 mmol) were combined in dry dichloromethane (100 ml) at 0° C. under argon. To the greenish suspension was added a solution of 2-naphthoyl chloride (5.0 g, 26 mmol) in dichloromethane (20 ml) at 0° C. over a period of 20 min to obtain a dark purple solution. The reaction was stirred for 2 h at room temperature and then quenched by careful addition of saturated aqueous ammonium chloride solution (100 ml). The organic layer was separated, washed with sat. aqueous sodium bicarbonate solution (2×30 ml), dried (MgSO₄) and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 1:1 pentane: diethyl ether by volume as eluent to give the ketone (5.6 g, 69%) as a red solid.

Step 2

The ferrocenyl ketone (4.5 g, 13.2 mmol) and borane dimethyl sulfide complex (1.4 ml, 14 mmol) were added simultaneously over a period of 30 minutes to a solution of the CBS catalyst (0.70 g, 2.5 mmol) in THF (80 ml) at 0° C. under argon. CBS catalyst is

The catalyst is prepared from 1,1-diphenyl pyrrolidine methanol and borane (see Synlett 1993, 929).

After stirring for an additional 30 min the mixture was quenched with aq. ammonium chloride solution (70 ml). The organic layer was separated, dried (MgSO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 1:1 pentane:ether as eluent affording the desired alchohol (4.0 g, 89%) as an orange solid.

Step 3

The ferrocenyl alcohol (4.0 g, 11.6 mmol) was dissolved in dry pyridine (30 ml) and acetic anhydride (20 ml) at room temperature. After stirring for 18 h at room temperature all volatiles were removed under high vacuum at 50° C. furnishing the pure acetylated alcohol (4.5 g, 100%) as a red glue, that smoothly crystallised on standing to a red solid.

The acetylated alcohol (3.0 g, 8 mmol) was dissolved in acetonitrile (200 ml) and 37% aqueous ammonia solution (40 ml). After stirring for 24 h at room temperature the mixture was poured into 10% aqueous hydrochloric acid (200 ml). The resulting precipitate was removed by filtration and washed with ether (4×20 ml). The residue was dissolved in 20% aqueous sodium hydroxide solution (200 ml) and the desired product re-extracted with ether (5×50 ml). After drying (MgSO₄), the solvent was removed under reduced pressure and the pure (R)-(1-amino-2-naphthylmethyl) ferrocene (1.8 g, 66%) was obtained as an orange solid.

The corresponding compounds in which the naphthyl group is replaced by phenyl, o-tolyl, 1-naphthyl, 2-naphthyl, methyl, cyclohexyl, o-biphenyl, p-biphenyl, phenanthrenyl, o-bromophenyl and p-butylphenyl were prepared similarly. Compounds in which the ferrocenyl is symmetrically 1,1′ disubstituted with 1-aminobenzyl, 1-amino-2-naphthylmethyl, 1-amino-(4-tert-butylphenyl)methyl, or 2-substituted with trimethylsilyl were prepared using the method given in example 1 except that two mole equivalents of aluminium chloride and acylchloride were used in step 1, two mole equivalents borane dimethylsulfide and 30 mol % CBS catalyst were used in step 2, and two mole equivalents acetic anhydride, pyridine and ammonia were used in step 3. The enantiomeric excess was in each case greater than 99%.

The reaction is illustrated below. The reaction was also carried out with the compounds indicated below, the % figures indicating the stated yields of pure material based on starting material,

EXAMPLE 2 Enantioselective allylation. Preparation of (+)-(S)-5,5-dimethyl-3(4-trifluoromethylphenyl)-1-hexene

This reaction is shown below

The chiral organic ligand R⁷=ferrocenyl, R⁸=2-naphthyl (70 mg, 0.2 mmol) and CuBr.Me₂S (3 mg, 0.02 mmol) were dissolved in THF (5 ml) yielding a clear solution. After cooling to −90° C., neo-Pent₂Zn (0.3 ml, 2.4 mmol) and 4-trifluoromethylcinnamyl chloride were added successively. The reaction mixture was stirred for 18 h at −90° C. and was worked up. The crude residue obtained after evaporation of the solvents was purified by flash-chromatography (ether:pentane 1:50) leading to the desired product (370 mg, 72% yield: S_(N)2′/S_(N)2 ratio:97:3). The enantiomeric excess of the chiral product was determined by gas chromatography to be 87% using a Chiraldex capillary column.

Use of different substituents R⁷ and R⁸ in asymmetric allylation reaction

The following Table 1 shows the use of different chiral organic ligands (lig*) R⁷ and R⁸ as indicated in table 1, in the reaction of cinnamyl chloride with di-neopentyl zinc at −50° C. The chiral organic ligands were prepared according to the methods in example 1 and are of the (R) configuration. The experimental conditions are analogous to those in Example 2 above.

TABLE 1 Yield Entry R⁷ R⁸ % S_(N)2′:S_(N)2 ee 1 Ferrocenyl Phenyl 73 95:5 32% 2 Ferrocenyl o-Tolyl 79 96:4 16% 3 Ferrocenyl 1-Naphthyl 72 93:7 33% 4 Ferrocenyl 2-Naphthyl 77 95:5 42% 5 Ferrocenyl Methyl 74  88:12  7% 6 Ferrocenyl Cyclohexyl 74 92:8  15%¹ 7 Ferrocenyl o-Biphenyl n.d. 92:8  4% 8 Ferrocenyl p-Biphenyl 84 97:3 38% 9 Ferrocenyl Phenanthrenyl 69 98:2 61% 10 Ferrocenyl 2-Naphthyl 75 97:3 67% 11 Ferrocenyl o-Bromophenyl 67 96:4 38% 12 Ferrocenyl p-′Butylphenyl 69 96:4 56% 13

68 99:1 51% 14

68 97:3 52% 15

69 96:4 45% 16

66 98:2 11% 17 phenyl methyl >95  94:6 44% 18 2-naphthyl methyl >95  95:5 42% 19 1-naphthyl methyl >95  95:5 52% 20 R⁷ + R⁸ =  80%  86:14 18% (R)-2-bomyl 21 R⁷ + R⁸ = (R)1- >95% 93:7 16% indanyl 22 R⁷ + R⁸ = (S)-  70% >99:1   0% trans-2- cyclohexylamine 23 (S)-2- phenyl  70% >99:1   0% aminobenzyl Entry 1-8: Ratio CuBr Me₂S/Lig*/Substrate = 1/1/20. Entry 9-23:1/10/100 ¹Opposite stereoisomer in excess Use of different substrates for the substitution The following Tables 2 and 3 show the use of different allyl reagents R¹ and R² and (except in entry 13 of Table 3) R³ = H, R⁴ and R⁵ as indicated in the tables, in the reaction with di-neopentyl zinc using the chiral ligand R⁷ = ferrocenyl, R⁸ = 2-naphthyl of the (R) configuration. The experimental conditions are analogous to those in Example 2 above.

Reactions run at −50° C.

TABLE 2 Reactions run at −50° C. Yield Entry R⁴ R⁵ (%) S_(N)2':S_(N)2 ee 1 H phenyl 75 97:3 67% 2 phenyl H 50 96:4 22% 3 H 2-trifluoro- 55  80:20 —¹ methyl phenyl) 4 H 4-trifluoro- 70 98:2 74% methyl phenyl) 5 H 1-naphthyl 74 97:3 58% 6 H cyclohexyl 70  (78:22) 59% 7 H phenylmethyl 50  18:82  4% 8 CH₂OMe H 67 >99:1   2% 9 CH₂OAc H 74 >99:1  14% 10 CH₂OSitBuMe₂ H 30 >99:1  29% 11 CH₂OSi(iPr)₃ H 53 >99:1  47% 12 H CH₂Osi(ipr)₃ 55 >99:1  38% 13 CH₂OSiPh₂tBu H 70 >99:1  12% ¹Separation of enantiomers was not possible.

Reactions run at −90° C.

TABLE 3 Reactions run at −90° C. Yield Entry R⁴ R⁵ R³ (%) S_(N)2':S_(N)2 ee 1 H phenyl H 68 95:5 82% 2 H 4-trifluoromethyl phenyl H 72 97:3 87% 3 H 1-naphthyl H 65 94:6 71% 4 H 2-naphthyl H 60 91:9 70% 5 H cyclohexyl H 67 98:2 76% 6 H 3-thienyl H 70 94:6 63% 7 CH₂OSi(iPr)₃ H H 45 >99:1  64% 8 H 4-isopropylphenyl H 70  90:10 76% 9 H 4-chlorophenyl H 71 96:4 79% 10 H 3-chlorophenyl H 72 97:3 70% 11 H 3,4-dichlorophenyl H 68 96:4 22% 12 H 1-cyclopentenyl H 63  64:36 60% 13 phenyl H —CO₂Et 71  87:13 12%

Use of different diorganozincs at −50° C.

The following Table 4 shows the use of different organozinc reagents Zn(R⁶)₂, in the reaction with trans-cinnamyl chloride using the chiral ligand R⁷=ferrocenyl, R⁸=2-naphthyl of the (R) configuration. The experimental conditions are analogous to those in Example 2 above.

TABLE 4 Entry R⁶ Yield (%) S_(N)2′:S_(N)2 ee 1 Methyl 90 98:2 10% 2 Ethyl 88 98:2 10% 3 isoPropyl 87 98:2 29% 4 isoButyl 69 98:2 45% 5 Pentyl 88 98:2 26% 6 neoPentyl 75 97:3 67% 7 1R-(+)-Pinane 65 97:3 41% 8 1S-(−)-Pinane 60 98:2 37% 9 PhMe₂SiCH₂ 50 90:10 42% 10 Me₃SiCH₂ 52 94:6 67% 11 Me₂PhCCH₂ —¹ 68:32 25% 12 Me₂PhSi(CH₂)₂ 78 98:2 15% 13 H₂C═CH₂C(CH₃)₂CH₂ 65 95:5 79%² ¹Reaction worked up before completion. ²Reaction done at −85° C. 

What is claimed is:
 1. A process in which an allylic compound is reacted with an organozinc compound to eliminate a group (the leaving group) from the allylic compound and to add a group from the organozinc compound to it in the presence of a copper salt catalyst and a chiral organic ligand for the copper.
 2. A process as claimed in claim 1 in which the allylic compound is of formula

where X is the leaving group and in which A is hydrogen or an alkyl or aryl group, having 1-20 carbon atoms.
 3. A process as claimed in claim 1 or 2 in which S_(N)2′ substitution giving a chiral centre occurs.
 4. A process as claimed in either claim 1 or claim 2 in which the reaction is stereospecific.
 5. A process as claimed in claim 1 in which the reaction is as follows

wherein R¹-R⁶ are alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl groups optionally substituted by halogen, alkoxy, aryloxy, acyloxy, nitro, amide, acetamide, carboxylate, cyano, acetal, sulphide, sulphonate, sulfone, sulfoxide, phosphite, phosphonate, phosphine groups, each having at most 20 carbon atoms or R¹ to R⁵ may be H, R⁷ is an aryl and R⁸ is an alkyl or aryl, which may be substituted, X is halogen, OR⁹, OCOR⁹, OCO₂R⁹, OSO₂R⁹ , OCS₂R⁹ CH(OR¹⁰)₂, OPO (OR⁹)₂, SOR⁹, or SO₂R⁹ in which R⁹ and R¹⁰ are optionally substituted C₁-C₁₀ alkyl or aryl, Y is halogen, carboxylate, cyanide, or thiocyanate and Z is an ether or thioether.
 6. A process as claimed in claim 5 in which R⁸ is aryl optionally substituted by a halogen or haloalkyl group.
 7. A process as claimed in claim 5 in which R¹, R², R³ and one of R⁴ and R⁵ are hydrogen the other of R⁴ and R⁵ is an aryl or trialkylsilyloxymethyl group, R⁶ is an alkyl group and R⁷ is a ferrocenyl group, R⁸ is an aryl group.
 8. A process as claimed in claim 6 in which R⁸ is a naphthyl or substituted naphthyl group.
 9. A process as claimed in claim 5 in which X is chlorine and Y is chloride or bromide.
 10. A process as claimed in claim 5 in which R¹, R², R³ and one of R⁴ and R⁵ are hydrogen, and in which the other of R⁴ and R⁵ is a phenyl,4-chlorophenyl, 4-trifluoromethyl phenyl, or trialkyl silyl oxy methyl group.
 11. A process as claimed in claim 5 in which one of the groups R⁷ or R⁸ is a ferrocenyl or substituted ferrocenyl group and the other is a naphthyl or substituted naphthyl group.
 12. A process as claimed in claim 5 in which R⁵ is a phenyl group and R⁶ is a neopentyl group.
 13. A process as claimed in claim 1 or claim 2 in which an alkane, cyclo alkane and/or aromatic solvent is present.
 14. A process as claimed in claim 1 or claim 2 in which an ether is present as a solvent.
 15. A process as claimed in claim 14 in which the ether is diethylether, 1,4-dioxane, tertbutylmethylether, or tetrahydrofuran.
 16. A process as claimed in claim 1 or claim 2 which is carried out at a temperature of −90° C. to −50° C.
 17. A process as claimed in claim 1 or claim 2 in which the concentration of the catalyst is in the range 0.5 to 5 atom %, expressed as copper atoms based on moles of the allylic compound.
 18. A process as claimed in claim 1 or claim 2 in which the ratio of copper atoms to the amine ligand molecules is 1:10 to 2:1.
 19. A compound of formula

in which A is a ferrocenyl or substituted ferrocenyl group and B is an aryl group other than a phenyl group.
 20. A compound as claimed in claim 19 in which B is a 2-naphthyl group.
 21. A complex which comprises a compound of formula

in which A is a ferrocenyl or substituted ferrocenyl group and B is an alkyl group or aryl group other than a methyl group or phenyl group, and copper.
 22. A complex according to claim 21, wherein B is an aryl group other than phenyl.
 23. A complex according to claim 21, wherein B is a 2-naphthyl group.
 24. A process as claimed in claim 6 in which R⁸ is phenyl optionally substituted by a halogen or haloalkyl group.
 25. A process as claimed in claim 5 where each of R¹ to R⁶ have less than 10 carbon atoms.
 26. A process as claimed in claim 5 wherein R⁷ is phenyl or ferrocenyl or substituted aryl or ferrocenyl groups. 